Early Airway Response to Allergen in Asthmatics (MK-0000-176): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Early Airway Response to Allergen in Asthmatics (MK-0000-176) (NCT01061333), a randomized phase 1 study. The primary outcome is Change in Forced Expiratory Volume in 1 Second (FEV1).

2. Clinical Question

3. Trial Design

The registry describes NCT01061333 as a phase 1, randomized, double-masked, placebo-controlled crossover trial. Its official title identifies a two-part study of inhaled nedocromil, oral montelukast, and inhaled mometasone. The listed condition is asthma, and the recorded enrollment is 16. The study status is completed; the registry gives a start of 2010-06 and primary completion of 2011-02.

The placebo arm and the three active-treatment arms are all represented in the posted primary outcome results. Arm-level counts are 16 for placebo, 16 for nedocromil, 15 for montelukast, and 15 for mometasone. These are reported outcome counts; they should not be interpreted as a total number of distinct participants in a crossover design. The detailed treatment sequence, period structure, washout interval, and how the two parts relate to one another are not reported in the registry record.

In a crossover trial, participants receive treatment conditions in a sequence rather than being assigned to only one treatment for the entire study. This general design can support within-participant comparisons, but the posted summary does not describe the sequence or the model terms used to account for periods or treatment order. Double masking indicates that the trial was masked, but the record details do not specify which parties were masked.

The primary endpoint is a continuous measure: the maximal percent drop in FEV1 at 20 minutes after allergen challenge. The reported arm values are means with standard deviations. The registry also lists secondary outcomes concerning urinary 9P, urinary leukotriene E4, and sputum LTC4, LTD4, and LTE4. Numerical results for those secondary outcomes are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Period 1: Placebo Run-in

Period 2: 20-day Washout

Period 3: Nedocromil-Montelukast X-over

Period 4: 20-day Washout

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change in Forced Expiratory Volume in 1 Second (FEV1), measured over Pre-allergen challenge and 20 minutes after allergen challenge.

The primary endpoint is the maximal percent drop in forced expiratory volume in one second (FEV1) at 20 minutes after allergen challenge, assessed in relation to the pre-allergen measurement. FEV1 measures the volume of air a person can forcefully exhale in one second. In this study, the endpoint describes the size of the early change in lung function after the allergen challenge; it is not a measure of long-term asthma control.

The registry expresses the arm results as means and standard deviations. The arm means are negative, consistent with the endpoint being a drop from the pre-challenge measurement. The reported comparison is a difference in least-squares means between each active-treatment arm and placebo. A positive difference in this context corresponds to a less negative mean drop in the active-treatment arm than in the placebo arm, as reflected by the posted arm means. The registry reports the comparison values and their confidence intervals in its ANCOVA analyses.

FEV1 provides a continuous measure of the airway response, allowing the analysis to describe both the direction and magnitude of changes across the treatment conditions. The plasma 9α-11ß-PGF2 marker, also called 9P in the brief summary, is mentioned as an assessed marker, but it is not the stated primary endpoint. The numerical outcome results for that marker are not reported in the registry record.

7. Results Posted in the Registry

• Nedocromil: mean -8.44 versus -24.66 on control; difference 16.22 (95% CI 10.16 to 22.28), standardized effect d = 1.86; z-test p = <0.001.
• Montelukast: mean -9.15 versus -24.66 on control; difference 15.51 (95% CI 9.19 to 21.83), standardized effect d = 1.70; z-test p = <0.001.
• Mometasone: mean -16.17 versus -24.66 on control; difference 8.49 (95% CI 0.83 to 16.15), standardized effect d = 0.78; z-test p = 0.030.

8. Statistical Interpretation

9. Statistical Methods Explained

What does an ANCOVA comparison represent?

The registry reports analysis of covariance (ANCOVA) for each comparison of an active-treatment arm with placebo. In general, ANCOVA estimates a difference between groups while accounting for covariates included in the model. The reported parameter is a difference in least-squares means. A least-squares mean is a model-based group mean, adjusted according to the variables included in that model; it is not necessarily identical to the raw arithmetic mean. The registry record does not report the covariates, model formula, or detailed assumptions, so those aspects cannot be evaluated from the registry entries.

The primary outcome is continuous, and the arm-level results are reported as means with standard deviations. A standard deviation describes the spread of observations around a group mean. It is not the same as a confidence interval, which describes uncertainty around an estimated quantity. The registry lists means of -24.66 for placebo, -8.44 for nedocromil, -9.15 for montelukast, and -16.17 for mometasone. Their reported standard deviations are 10.72, 6.15, 6.96, and 11.01, respectively.

How should the recalculated comparisons be read?

The recalculated comparisons are simple, unadjusted re-calculations from the posted summary statistics. They are not the sponsor's ANCOVA analysis and do not reproduce any adjustment or crossover-specific modelling that may have been used. The recalculated mean differences are 16.22 for nedocromil, 15.51 for montelukast, and 8.49 for mometasone. Their recalculated confidence intervals are 10.16 to 22.28, 9.186 to 21.83, and 0.833 to 16.15, respectively; the associated unadjusted p-values are <0.001, <0.001, and 0.03.

These recalculations use approximate pooled standard deviations, as indicated in the posted calculation details. In general, a pooled standard deviation combines information about spread across groups for a simple comparison. That approach does not account for within-participant correlation in a crossover trial. If paired participant-level data and the trial's analysis model are unavailable, a summary-statistic re-calculation may not reflect the precision of a crossover analysis. It should therefore be kept distinct from the registry's reported ANCOVA results.

What does a confidence interval tell the reader?

In general, a confidence interval gives a range of estimates compatible with the observed data under the statistical method and its assumptions. A narrower interval indicates greater statistical precision than a wider interval, all else equal. It does not mean that there is a specified probability that the true value lies in the particular interval after the interval has been calculated. For this trial, the sponsor-reported intervals are 90% confidence intervals; the confidence level for the simple recalculated intervals is not stated in the registry record for the results.

What do the p-values mean?

In general, a p-value measures how surprising data at least as extreme as those observed would be under a specified null hypothesis and statistical model. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The sponsor-reported values are tied to the ANCOVA analyses. Separate recalculated p-values are unadjusted and should not be confused with the sponsor's results. The record details do not report whether the analyses account for testing multiple comparisons.

What matters about the crossover design?

In general, crossover designs can use comparisons within participants, which may help account for stable differences between people. Their analysis may also need to address period, treatment sequence, and possible carryover effects. The registry identifies this as a crossover trial, but does not report sequence assignments, period-specific results, washout details, or how the ANCOVA handled the crossover structure. Those omissions prevent a fuller assessment of how the reported estimates reflect the design.

The record lists 8 outcome measures and 24 analyses, but a multiplicity strategy is not reported in the registry record. The registry entries also do not report an analysis population definition or missing-data procedures. Without those details, the reader cannot determine from the registry record whether all intended outcomes, comparisons, and participants were handled according to a prespecified statistical plan.

10. Confidence Intervals and Precision

The sponsor-reported ANCOVA estimates are 16.22 for nedocromil versus placebo, 15.51 for montelukast versus placebo, and 8.49 for mometasone versus placebo. Their 90% confidence intervals are 10.74 to 21.69, 10.00 to 21.02, and 1.78 to 15.20, respectively. Each interval is entirely above zero. The mometasone interval is closer to zero at its lower end than the other two intervals, while all three retain a range of plausible effect sizes rather than identifying a single exact value.

In general, a confidence interval reflects both the estimated contrast and its statistical uncertainty under the model used. The interval's width is one indication of precision: a narrower interval generally indicates a more precise estimate, while a wider interval indicates greater uncertainty. A confidence interval does not capture all possible sources of uncertainty, including limitations from study design, analysis choices, or incomplete reporting.

The registry also allows simple unadjusted recalculations from the summary statistics. Their intervals are 10.16 to 22.28 for nedocromil, 9.186 to 21.83 for montelukast, and 0.833 to 16.15 for mometasone. These are not the sponsor's ANCOVA intervals. The sponsor analysis is the registry's reported inferential analysis; the recalculated intervals use approximate pooled standard deviations and do not reproduce details of the ANCOVA or the crossover analysis.

The arm-level counts are 16 for placebo and nedocromil and 15 for montelukast and mometasone. With these small arm-level counts, estimates can remain uncertain even when a reported interval excludes zero. The registry does not report additional precision measures for the secondary outcomes, and their numerical results are not reported in the registry record.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations derived from the observed effect, not a record of the trial's original sample-size design. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to a stated fraction of the observed effect. The registry's original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the planned number of participants per arm under the stated assumptions for an 80% chance of detecting the chosen effect if that effect is present and the model assumptions hold. The 90% power column gives the corresponding number per arm for a higher chance of detection under those same assumptions. These are planning targets, not observed power; observed power is not an interpretation of the trial's results.

The planning display gives values for detecting the full observed effect, 75% of the observed effect, and 50% of the observed effect. For nedocromil, those figures are 5 and 7, 9 and 11, and 19 and 25 participants per arm for 80% and 90% power, respectively. For montelukast, they are 6 and 8, 10 and 13, and 22 and 29. For mometasone, they are 26 and 35, 46 and 62, and 103 and 138.

Smaller target effects require more participants per arm under these assumptions because they are harder to distinguish statistically from random variation. These values are planning illustrations based on the observed effects, not proof that the trial was designed with those targets or that the observed analyses had a particular probability of detecting an effect.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 16.220; pooled standard deviation σ = 8.739.
2. n = 2 × (1.96 + 0.842)² × 8.739² / 16.220² = 4.6, rounded up to 5 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 16.22                      # observed difference in means
sigma <- 8.73901882364376                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1061333)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 5 (80% power), 7 (90% power)
 75% of observed effect: n per arm = 9 (80% power), 11 (90% power)
 50% of observed effect: n per arm = 19 (80% power), 25 (90% power)
power.t.test: 5.7 
Simulated power at n = 5 per arm: 0.732 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry's reported primary analyses are the sponsor's ANCOVA comparisons, expressed as differences in least-squares means with 90% confidence intervals and p-values. Those estimates are 16.22 for nedocromil versus placebo, 15.51 for montelukast versus placebo, and 8.49 for mometasone versus placebo. The respective reported p-values are < 0.001, < 0.001, and 0.043.

The simple recalculated comparisons use posted arm-level summary statistics and approximate pooled standard deviations. They are unadjusted and do not reproduce the sponsor's ANCOVA model or account for any crossover-specific structure. Their estimates match the reported contrasts, but their confidence intervals and p-values differ from the sponsor-reported analysis. This is not a flagged discrepancy in the record. The sponsor's own analysis therefore remains the principal reported inferential analysis, while the recalculations serve only as a separate summary-statistic check.

The registry record does not give the full ANCOVA specification, including its covariates or treatment of crossover periods. Consequently, the recalculations cannot establish why the reported uncertainty measures differ or whether the underlying models share assumptions. The sponsor results should be read as the registered analysis results, with their model details and limitations recognized as not fully reported in the registry record.

14. Multiplicity, Missing Data and Analysis Populations

The record lists 8 outcome measures and 24 analyses. It identifies the primary endpoint as maximal percent drop in FEV1 at 20 minutes after allergen challenge and lists secondary outcomes involving urinary 9P, urinary leukotriene E4, and sputum LTC4, LTD4, and LTE4. Numerical results for those secondary outcomes are not reported in the registry record.

When multiple outcomes or comparisons are tested, the chance of at least one apparently notable result can increase. In general, a multiplicity procedure can control or otherwise address that issue, but the registry record does not report a multiplicity adjustment, a testing hierarchy, or which analyses were considered confirmatory. The reported p-values should therefore be read as the values attached to the individual reported ANCOVA comparisons, without assuming that they were adjusted for the full set of analyses.

The record details do not describe missing-data handling, how participants were included in each analysis, or the analysis population definitions. Arm-level outcome counts differ across the listed arms, but the registry does not explain the reasons for those counts or whether any data were missing. The record also does not report how incomplete crossover periods or unavailable measurements were handled.

Other details relevant to interpretation are not reported in the registry record: the original sample-size rationale, the prespecified statistical analysis plan, the ANCOVA covariates and model specification, and how treatment sequence, period, or possible carryover effects were addressed. The record does not report interim analyses. These are limits on what can be determined from the posted registry results; they do not establish that such procedures were or were not used outside the information reported in the registry record.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures report zero affected participants for placebo, nedocromil, montelukast, and mometasone. The corresponding numbers at risk are 16, 16, 15, and 15. No serious adverse event terms are listed among the top serious terms.

These figures describe the serious adverse event counts recorded for the listed groups. A zero count means no serious adverse events were recorded for that group in these results; it does not establish that the risk of serious events is absent. The study has small arm-level counts, so the safety figures should be interpreted as limited observations rather than precise estimates of uncommon risks.

The registry also provides counts for other adverse events: 5 for placebo, 4 for nedocromil, 3 for montelukast, and 0 for mometasone. These are separate from the serious adverse event counts. Death counts are not reported in the registry record. The safety data do not by themselves establish comparative safety beyond the events recorded in this trial.

16. What the Result Does, and Does Not, Mean

The posted results describe the early airway response to allergen challenge after pretreatment with nedocromil, montelukast, or mometasone, compared with placebo. For the primary endpoint, each active-treatment arm has a less negative mean percent drop in FEV1 than placebo. The sponsor-reported ANCOVA contrasts are positive, and their 90% confidence intervals are above zero. These are findings about the trial's measured short-term response under its study conditions.

The results do not establish the effects of these drugs on long-term asthma outcomes, everyday symptoms, exacerbations, or quality of life. The endpoint is a response at 20 minutes after allergen challenge, not a measure of long-term disease management. Nor do the results establish how the estimates would apply to people outside the trial population or to other dosing and treatment contexts.

Statistical evidence and clinical importance are different questions. In general, a p-value addresses compatibility with a null hypothesis under a statistical model; it does not state the size or practical importance of an effect. The confidence intervals describe uncertainty around the estimated differences, but they do not resolve limitations due to small arm-level counts, unreported model details, or unreported multiplicity handling.

The registry identifies a randomized, double-masked crossover design, but does not report the treatment sequence, period structure, washout, or crossover-specific analysis details. Those omissions constrain assessment of how the design informed the estimates. The trial also lists secondary biomarker outcomes, but their numerical results are not reported in the registry record. Conclusions should therefore remain focused on the posted primary FEV1 comparisons and their limits.

17. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates how a continuous physiological endpoint can be reported through both group summaries and model-based comparisons. The arm means and standard deviations describe the observed outcome distributions at a basic level, while ANCOVA differences in least-squares means provide the registry's adjusted comparisons against placebo. Reading both types of results helps distinguish descriptive summaries from inferential estimates.

The crossover design also makes analysis details especially relevant. In general, a crossover can use within-participant information, but the interpretation depends on treatment sequence, period structure, and how the analysis accounts for those features. The registry identifies the design without reporting those details. This makes the record a useful reminder that a design label alone does not explain the statistical model used.

The comparison between sponsor-reported ANCOVA results and simple summary-statistic recalculations illustrates another important point: calculations that appear to target the same contrast can yield different uncertainty measures when their methods differ. The recalculations are unadjusted, whereas the posted sponsor results are ANCOVA estimates. Keeping those analyses distinct avoids treating a simplified check as a replacement for the trial's reported analysis.

Finally, the study demonstrates why precision and multiplicity matter alongside p-values. The small arm-level counts and confidence intervals give context for the size and uncertainty of the primary estimates. The record lists multiple outcomes and analyses, while multiplicity handling and secondary numerical results are not reported. This limits how broadly the individual p-values can be interpreted.

18. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The posted outcome counts are small, with 16 reported for placebo and nedocromil and 15 for montelukast and mometasone. The trial is labeled phase 1, and its primary endpoint is a short-term response to allergen challenge. These features limit how broadly the findings can be generalized, particularly to longer-term outcomes or populations not described in the record details.

Important crossover details are not reported in the registry record, including treatment sequences, period-specific information, washout timing, and how the analysis addressed period or carryover effects. The ANCOVA model specification and covariates are also not reported. Without those details, a reader cannot assess fully how the reported model relates to the crossover design.

The registry does not report the original sample-size justification, multiplicity approach, analysis population definitions, or missing-data procedures. It lists 8 outcome measures and 24 analyses, but numerical results for the listed secondary outcomes are not reported in the registry record. These gaps constrain evaluation of the analysis plan and the overall pattern of findings.

The simple recalculations rely on summary statistics and approximate pooled standard deviations, not participant-level data or the sponsor's model. They cannot account for within-participant correlation in a crossover analysis. The sponsor ANCOVA results are therefore the primary posted inferential results, while the recalculations provide only a separate unadjusted comparison.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Early Airway Response to Allergen in Asthmatics (MK-0000-176) — NCT01061333.
• Registry record last updated 2015-09-04; status last verified 2015-09.
• Results first posted 2012-05-28.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

NCT01061333 is a completed phase 1, randomized, double-masked, placebo-controlled crossover trial in asthma, with recorded enrollment of 16. The primary endpoint is maximal percent drop in FEV1 at 20 minutes after allergen challenge. The registry reports ANCOVA differences in least-squares means against placebo for nedocromil, montelukast, and mometasone, with 90% confidence intervals and p-values.

The posted arm-level means are -24.66 for placebo, -8.44 for nedocromil, -9.15 for montelukast, and -16.17 for mometasone. The registry also lists secondary biomarker outcomes, but their numerical results are not reported in the registry record. Serious adverse event counts are zero in each listed group. Crossover analysis details, multiplicity handling, missing-data procedures, and the original sample-size rationale are not reported in the registry record.